The invention relates to the use of certain aminocarbonyl-substituted benzimidazole derivatives for the treatment of diseases in which inhibition of tryptase is of therapeutic value, certain novel aminocarbonyl-substituted benzimidazole derivatives having tryptase-inhibitory activity, methods for preparing their preparation and pharmaceutical compositions containing such compounds.
Benzimidazole derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles, which can be used to good effect, on the basis of their thrombin-inhibiting activity, to prevent and treat venous and arterial thrombotic diseases.
In contrast to the use of benzimidazole derivatives described hereinbefore and known from the prior art, the aim of the present invention is to prepare new tryptase inhibitors which can be used, by virtue of their tryptase-inhibiting properties, to prevent and treat inflammatory and/or allergic diseases.
It has been found, surprisingly, that aminocarbonyl-substituted benzimidazole derivatives of general formula (I)

 
wherein the groups R1, R2, R3 and R4 may have the meanings given hereinafter, have a tryptase-inhibiting effect and may be used according to the invention for the prevention and treatment of diseases in which tryptase inhibitors may be of therapeutic value.
Thus, a first aspect of the invention is a method for treating diseases in which tryptase inhibitors may be of thereapeutic value, which method comprises the administration, to a host in need of such treatment, of a thereapeutic amount of a compound of the formula (I)

 
wherein:
R1 denotes C1-C10-alkyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkoxy, phenoxy, hydroxyphenoxy, C1-C4-alkoxy-phenoxy, C3-C6-cycloalkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C4-alkyl) or xe2x80x94NHxe2x80x94CO-benzyl, or
phenyl-C1-C4-alkyl, wherein the phenyl ring may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a 5 or 6 membered, saturated or unsaturated heterocyclic group linked via a single bond or via a C1-C4-alkylene bridge, which may contain one, two or three heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, optionally by C1-C4-alkyl substituted phenyl or optionally by C1-C4-alkyl substituted benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 and R4 which may be identical or different, denote hydrogen, C1-C6-alkyl, which may be mono- or disubstituted by one or more of the groups COOH, COOxe2x80x94C1-C4-alkyl, C3-C6-cycloalkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C1-C4-alkyl, wherein the C1-C4-alkylene bridge may optionally be substituted by phenyl, COOH or COOxe2x80x94C1-C4-alkyl and wherein the phenyl ring may optionally be mono-, di- or tri-substituted, directly or via a C1-C4-alkylene bridge, by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, CF3, fluorine, chlorine, bromine, COOH, COOxe2x80x94C1-C4-alkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may contain one, two, three or four heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, phenyl or benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms, or
C3-C8-cycloalkyl, naphthyl or phenyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, phenyloxy, benzyloxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
R3 and R4 together with the nitrogen atom form a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two further heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be substituted by one or more of the groups C1-C4-alkyl, C5-C6-cycloalkyl, benzyl, which may optionally be substituted by C1-C4-alkyl, pyridyl or phenyl, optionally substituted by C1-C4-alkyl, C1-C4-alkoxy or hydroxy,
or a tautomer or pharmacologically acceptable acid addition salt thereof.
The phrase xe2x80x9ca host in need of such treatmentxe2x80x9d as used herein means a patient, whether animal or human, which or who suffers from a disease which is treatable by the inhibition of tryptase.
The above-described thereapeutic method may be used to treat inflammatory and/or allergic diseases. Even more particularly, the above-described method may be used for the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
The compounds of formula (I) as described above for may also be used, in accordance with the invention, for the treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.
Some of the above-described compounds of the formula (I) are known and others are novel. These novel compounds of formula (I) constitute a second aspect of the invention.
The novel compounds provided by the invention are those of the formula (I)

 
wherein
R denotes C1-C10-alkyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkoxy, phenoxy-, C1-C4-alkoxy-phenoxy, hydroxyphenoxy, C3-C6-cycloalkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C4-alkyl) or xe2x80x94NHxe2x80x94CO-benzyl, or
phenyl-C1-C4-alkyl, wherein the phenyl ring may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a 5 or 6 membered, saturated or unsaturated heterocyclic group linked via a single bond or via a C1-C4-alkylene bridge, which may contain one, two or three heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and
may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, optionally by C1-C4-alkyl substituted phenyl or optionally by C1-C4-alkyl substituted benzyl, or to which a benzene ring may optionally be fused via two adjacent carbon atoms;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes C1-C6-alkyl, which is mono- or disubstituted by one or more of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or benzyl, wherein the phenyl ring is mono- or disubstituted, directly or via a C1-C4-alkylene bridge, by one or more of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C2-C4-alkyl, wherein the C2-C4-alkylene bridge may optionally be substituted by phenyl, COOH or COOxe2x80x94C1-C4-alkyl and wherein the phenyl ring may optionally be mono- or di-substituted, directly or via a C1-C4-alkylene bridge, by one or more of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5 or 6 membered, saturated or unsaturated heterocyclic group linked via a C1-C4-alkylene bridge, which may contain one, two or three heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, phenyl or benzyl;
R4 denotes hydrogen, C1-C6-alkyl, which may be mono- or disubstituted by one or more of the groups COOH, COOxe2x80x94C1-C4-alkyl or C3-C6-cycloalkyl, or
phenyl-C1-C4-alkyl, wherein the C1-C4-alkylene bridge may optionally be substituted by phenyl and wherein the phenyl ring may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
C3-C8-cycloalkyl, naphthyl or phenyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, phenyloxy, benzyloxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked via a C1-C4-alkylene bridge, which contains a heteroatom selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C1-C4-alkyl, phenyl or benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms, or
R3 and R4 together with the nitrogen atom form a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group, which contains one or two further heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be substituted by one or more of the groups C1-C4-alkyl; benzyl, which is optionally C1-C4-alkyl-substituted, C5-C6-cycloalkyl, pyridyl or phenyl, which optionally bears a group selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Preferred are compounds of general formula (I), wherein
R1 denotes unsubstituted C1-C10-alkyl, or
may be mono- or disubstituted by C1-C4-alkoxy, phenoxy, C1-C4-alkoxy-phenoxy, hydroxyphenoxy, C3-C6-cycloalkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C4-alkyl) or NHxe2x80x94CO-benzyl substituted C1-C4-alkyl, or
phenyl-C1-C3-alkyl, wherein the phenyl ring may optionally be mono- or disubstituted by C1-C4-alkyl, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked via a C1-C3-alkylene bridge, which may contain one or two heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl, methylphenyl- or benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes C1-C6-alkyl, which is mono- or disubstituted by one or more of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
benzyl, wherein the phenyl ring is substituted directly or via a C1-C4-alkylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C2-C4-alkyl, wherein the C2-C4-alkylene bridge may optionally be substituted by phenyl, COOH or COOxe2x80x94C1-C4-alkyl and wherein the phenyl ring may be substituted directly or via a C1-C4-alkylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked via a C1-C4-alkylene bridge, which may contain one or two heteroatoms selected from the group comprising oxygen or nitrogen and may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl or benzyl;
R4 hydrogen, C1-C4-alkyl, which may be substituted by one of the groups COOH, COOxe2x80x94C1-C4-alkyl or C3-C6-cycloalkyl, or
phenyl-C1-C4-alkyl, wherein the C1-C4-alkylene bridge may optionally be substituted by phenyl and wherein the phenyl ring may optionally be mono- or disubstituted by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
C3-C8-cycloalkyl, naphthyl or phenyl, which may optionally be mono- or disubstituted by one or more of the groups C1-C4-alkyl, C1-C4-alkoxy, phenyloxy, benzyloxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked via a C1-C4-alkylene bridge, which contains a heteroatom selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl or benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms, or
R3 and R4 together with the nitrogen atom form a 6- or 7-membered, saturated or unsaturated heterocyclic group, which contains one or two further heteroatoms selected from the group comprising oxygen or nitrogen and which may optionally be substituted by one or more of the groups methyl, ethyl, propyl, benzyl, cyclopentyl, cyclohexyl, pyridyl or phenyl, which optionally carries a group selected from the group comprising methyl, methoxy, ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
More preferred are compounds of general formula (I), wherein
R1 denotes unsubstituted C1-C10-alkyl, or by C1-C4-alkoxy, phenoxy, C1-C4-alkoxy-phenoxy, hydroxyphenoxy, C3-C6-cycloalkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4-alkyl), xe2x80x94COxe2x80x94NH2, xe2x80x94CO-NHxe2x80x94(C1-C4-alkyl) or xe2x80x94NHxe2x80x94CO-benzyl substituted C1-C4-alkyl, or
phenyl-C1-C3-alkyl, wherein the phenyl ring may optionally be mono- or disubstituted by C1-C4-alkyl, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C4-alkyl, or
a heterocyclic group linked via a C1-C3-alkylene bridge, optionally mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl, methylphenyl or benzyl, selected from the group comprising pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, pyrimidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolan, dithiolan, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzodioxole, benzimidazole, benzothiophene, benzofuran or indole;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes C1-C3-alkyl, which is substituted by xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C3-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C3-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
benzyl, wherein the phenyl ring is substituted directly or via a methylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C3-alkyl), xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C2-C3-alkyl, wherein the C2-C3-alkylene bridge may optionally be substituted by phenyl, COOH or COOxe2x80x94C1-C3-alkyl and wherein the phenyl ring may be substituted directly or via a methylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C3-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a heterocyclic group linked via a C1-C3-alkylene bridge, optionally mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl or benzyl, selected from the group comprising pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, pyrimidine, piperazine morpholine, diazepan, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxane, oxazole or isoxazole;
R4 denotes hydrogen, C1-C4-alkyl, which may be substituted by one of the groups COOH, COOxe2x80x94C1-C3-alkyl or C3-C6-cycloalkyl, or
phenyl-C1-C3-alkyl, wherein the C1-C3-alkylene bridge may optionally be substituted by phenyl and wherein the phenyl ring may optionally be substituted by C1-C3-alkyl, C1-C3-alkoxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C3-alkyl, or
C3-C8-cycloalkyl, naphthyl or phenyl, which may optionally be mono- or disubstituted by one or more of the groups C1-C3-alkyl, C1-C3-alkoxy, phenyloxy, benzyloxy, CF3, fluorine, chlorine, bromine, COOH or COOxe2x80x94C1-C3-alkyl, or
a heterocyclic group linked via a C1-C3-alkylene bridge, optionally mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl, methylphenyl- or benzyl, selected from the group comprising pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, pyrimidine, piperazine morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolan, dithiolan, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzodioxole, benzimidazole, benzothiophene, benzofuran or indole; or
R3 and R4 together with the nitrogen atom form a 6- or 7-membered, saturated heterocyclic group, which contains one or two further nitrogen heteroatoms and which may optionally be substituted by one or more of the groups methyl, ethyl, propyl, benzyl, cyclopentyl, cyclohexyl, pyridyl or phenyl, which optionally carries a group selected from the group comprising methyl, methoxy, ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Still more preferred are compounds of general formula (I), wherein
R1 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, or
a methyl, ethyl or propyl group which is substituted by methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, methoxyphenoxy, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHxe2x80x94CO-methyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NH-methyl or xe2x80x94NHxe2x80x94CO-benzyl, or
benzyl, which is mono- or disubstituted by methyl, ethyl, propyl, CF3, fluorine, chlorine, bromine, COOH, COOMe or COOEt, or
phenylethyl, which is mono- or disubstituted by methyl, ethyl, propyl, CF3, fluorine, chlorine, bromine, COOH, COOMe or COOEt, or
a heterocyclic group linked via a methylene, ethylene or propylene bridge, optionally mono- or disubstituted by one or more of the groups methyl, ethyl, propyl, phenyl, methylphenyl or benzyl, selected from the group comprising pyrrole, pyrrolidine, pyridine, piperidine, piperazine, morpholine, furan, tetrahydrofuran, thiophene, benzodioxole or benzimidazole;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a methyl, ethyl or propyl group which is substituted by xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C3-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C3-alkyl), xe2x80x94NH-benzyl or xe2x80x94C(xe2x95x90NH)NH2, or
benzyl, which is substituted directly or via a methylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C3-alkyl) or xe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C2-C3-alkyl, wherein the C2-C3-alkylene bridge may optionally be substituted by phenyl, COOH or COOxe2x80x94C1-C3-alkyl and
wherein the phenyl ring may be substituted directly or via a methylene bridge by one of the groups xe2x80x94NH2, xe2x80x94NH(C1-C3-alkyl), xe2x80x94N(C1-C3-alkyl)2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2 or xe2x80x94C(xe2x95x90NH)NH2, or
a heterocyclic group linked via a methylene, ethylene or propylene bridge, optionally mono- or disubstituted by methyl, ethyl, propyl, phenyl or benzyl, selected from the group comprising pyrrole, pyrrolidine, pyridine, piperidine, piperazine, morpholine, diazepan, furan, tetrahydrofuran, thiophene, benzodioxole or benzimidazoles;
R4 denotes hydrogen or a methyl, ethyl, propyl or butyl group which may be substituted by one of the groups COOH, COOMe, COOEt, cyclopropyl, cyclopentyl or cyclohexyl, or
benzyl, which may optionally be substituted by methyl, ethyl, propyl, methoxy, ethoxy, CF3, fluorine, chlorine, bromine, COOH, COOMe or COOEt, or phenylethyl, phenylpropyl, diphenylpropyl;
cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, naphthyl or phenyl, which may optionally be substituted by methyl, ethyl, propyl, methoxy, ethoxy, phenyloxy, benzyloxy, CF3, fluorine, chlorine, bromine, COOH, COOMe or COOEt, or
a heterocyclic group linked via a methylene, ethylene or propylene bridge, optionally mono- or disubstituted by methyl, ethyl, propyl, phenyl or benzyl, selected from the group comprising pyrrole, pyrrolidine, pyridine, piperidine, piperazine, morpholine, furan, tetrahydrofuran, thiophene, quinoline, isoquinoline, benzodioxole or benzimidazole; or
R3 and R4 together with the nitrogen atom form a piperazine or diazepan ring which may optionally be substituted by one of the groups methyl, ethyl, propyl, cyclopentyl, cyclohexyl, pyridyl, benzyl or phenyl, which optionally carries a group selected from the group comprising methyl, methoxy ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Especially preferred according to the invention are compounds of general formula (I), wherein
R1 denotes methyl, ethyl, propyl, pentyl or n-decyl,
xe2x80x83or
a methyl, ethyl- or propyl group which is substituted by methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or methoxyphenoxy, or
benzyl, which is mono- or disubstituted by methyl, CF3, COOH, COOMe or COOEt,
xe2x80x83or
a tetrahydrofuran linked via a methylene bridge;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes an ethyl or propyl group which is substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94NHEt, xe2x80x94NEt2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2 or xe2x80x94C(xe2x95x90NH)NH2, or
benzyl which is substituted by one of the groups xe2x80x94NH2, xe2x80x94CH2xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NHMe, xe2x80x94NEt2, xe2x80x94NHEt, xe2x80x94NHxe2x80x94CO-Me, xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Me or xe2x80x94C(xe2x95x90NH)NH2, or
phenylethyl, wherein the ethylene bridge may be substituted by COOH, COOMe or COOEt and wherein the phenyl ring is optionally substituted by one of the groups xe2x80x94NH2, xe2x80x94CH2xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NHMe, xe2x80x94NEt2, xe2x80x94NHEt, xe2x80x94NHxe2x80x94CO-Me, xe2x80x94CH2xe2x80x94NHxe2x80x94CO-Me or xe2x80x94C(xe2x95x90NH)N2, or
phenylpropyl, diphenylpropyl or pyridylmethyl;
R4 denotes hydrogen or a methyl, ethyl, propyl or butyl group, which may be substituted by one of the groups COOH, COOMe, COOEt, cyclopropyl, cyclopentyl or cyclohexyl, or
benzyl, which may optionally be substituted by methyl, ethyl, propyl, methoxy, ethoxy, CF3, fluorine, chlorine, bromine, COOH, COOMe or COOEt, or phenyl-ethyl, phenylpropyl, diphenylpropyl, or
cyclopentyl, cyclohexyl, cyclooctyl, naphthyl or phenyl, which may optionally be substituted by methyl, ethyl, methoxy, ethoxy, phenyloxy or CF3, or
a pyridine or quinoline linked via a methylene bridge, or
R3 and R4 together with the nitrogen atom form a piperazine or diazepan ring, which may optionally be substituted by one of the groups cyclopentyl, cyclohexyl, pyridyl, benzyl or phenyl, which optionally carries one of the groups selected from the group comprising methyl, methoxy, ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
More especially preferred according to the invention are compounds of general formula (I), wherein
R1 denotes methyl, ethyl, propyl, pentyl, phenylethyl, phenylpropyl, cyclopropylmethyl, tetrahydrofuranylmethyl or benzyl, which is mono- or disubstituted by CF3, COOH, COOMe or COOEt;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes an ethyl or propyl group which is substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94NHEt, xe2x80x94NEt2, xe2x80x94NHphenyl, xe2x80x94N(phenyl)2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2 or xe2x80x94C(xe2x95x90NH)NH2,
or benzyl substituted by one of the groups xe2x80x94NH2, xe2x80x94CH2xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NHMe, xe2x80x94NEt2, xe2x80x94NHEt, xe2x80x94NHxe2x80x94CO-Me, xe2x80x94CH2xe2x80x94NHxe2x80x94CO-Me or xe2x80x94C(xe2x95x90NH)NH2,
or phenylethyl, wherein the ethylene bridge is substituted by COOH, COOMe or COOEt and wherein the phenyl ring carries one of the groups xe2x80x94NH2, xe2x80x94CH2xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NHMe, xe2x80x94NEt2, xe2x80x94NHEt, xe2x80x94NHxe2x80x94CO-Me, xe2x80x94CH2xe2x80x94NHxe2x80x94CO-Me or xe2x80x94C(xe2x95x90NH)NH2, or phenylpropyl, diphenylpropyl or pyridylmethyl;
R4 denotes hydrogen or a methyl, ethyl, propyl or butyl group which may be substituted by one of the groups COOH, COOMe, COOEt or cyclohexyl, or
phenyl, which may optionally be substituted by methyl, ethyl, methoxy, ethoxy, phenyloxy or CF3, or
benzyl, phenylethyl, phenylpropyl, diphenylpropyl, cyclohexyl, cyclooctyl or naphthyl, or
a pyridine or quinoline linked via a methylene bridge, or
R3 and R4 together with the nitrogen atom form a piperazine or diazepan ring, which may optionally be substituted by one of the groups cyclopentyl, cyclohexyl, pyridyl, benzyl or phenyl, which optionally carries a group selected from the group comprising methyl, methoxy, ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Still more especially preferred are compounds of general formula (I), wherein
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes ethyl, substituted by xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NHphenyl, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, pyrrolidine, piperidine, diazepan or xe2x80x94C(xe2x95x90NH)NH2, benzyl substituted by one of the groups xe2x80x94CH2xe2x80x94NH2, xe2x80x94NMe2 or xe2x80x94C(xe2x95x90NH)NH2, phenylethyl, wherein the ethylene bridge is substituted by COOH, COOMe or COOEt and wherein the phenyl ring carries one of the groups xe2x80x94CH2xe2x80x94NHxe2x80x94CO-Me or xe2x80x94C(xe2x95x90NH)NH2, diphenylpropyl or pyridylmethyl;
R4 denotes hydrogen or a methyl or ethyl group which may optionally be substituted by one of the groups COOH or COOEt; propyl, butyl or phenyl, which may optionally be substituted by methyl, ethyl, methoxy, ethoxy, phenyloxy or CF3; benzyl, phenylethyl, phenylpropyl, diphenylpropyl, cyclohexyl, cyclooctyl, naphthyl, pyridylmethyl or quinolinylmethyl or
R3 and R4 together with the nitrogen atom form a piperazine or diazepan ring substituted by one of the groups benzyl, cyclopentyl, cyclohexyl or phenyl, which optionally carries a group selected from the group comprising methyl, ethoxy, propyloxy or hydroxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Even more preferred are compounds of general formula (I), wherein
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes ethyl, substituted by xe2x80x94NH2, xe2x80x94NHphenyl, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, pyrrolidine, piperidine, diazepan or xe2x80x94C(xe2x95x90NH)NH2; benzyl substituted by xe2x80x94C(xe2x95x90NH)NH2, or diphenylpropyl;
R4 denotes hydrogen, methyl, propyl, butyl, benzyl or phenyl, which may optionally be substituted by ethyl or phenyloxy; phenylethyl, cyclohexyl or cyclooctyl, or
R3 and R4 together with the nitrogen atom form a piperazine ring which is substituted by a group selected from the group comprising cyclopentyl, cyclohexyl, phenyl, methylphenyl, ethoxyphenyl or propoxyphenyl, or a diazepan ring substituted by methylphenyl,
optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.
Penultimately preferred are those compounds of general formula (I) according to the invention wherein
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes ethyl, substituted by xe2x80x94NH2, xe2x80x94NHbenzyl, xe2x80x94N(benzyl)2, pyrrolidine, piperidine, diazepan or xe2x80x94C(xe2x95x90NH)NH2, benzyl substituted by xe2x80x94C(xe2x95x90NH)NH2, or diphenylpropyl;
R4 denotes hydrogen, methyl, butyl or phenyl, which may optionally be substituted by ethyl or phenyloxy; phenylethyl, cyclohexyl or cyclooctyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.
Ultimately preferred in accordance with the invention are the following specific compounds of the formula (I):
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carbonsxc3xa4ure-N-(2-amidinoethyl)-N-(2-phenylethyl)-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-[2-Nxe2x80x2,Nxe2x80x2-dibenzylamino)ethyl]-N-phenyl-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(2-amidinoethyl)-N-(3-phenoxy-phenyl)-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(2-amidinoethyl)-N-phenyl-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(2-amidinoethyl)-N-cyclooctyl-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(2-amidinoethyl)-N-(3-ethyl-phenyl)-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-[N-(2-(Nxe2x80x2-benzylamino)-ethyl)-N-cyclohexyl-amide];
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-[N-(2-amino-ethyl)-N-cyclohexyl-amide];
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(3,3-diphenylpropyl)-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(4-amidino-benzyl)-N-methyl-amide;
2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(2-amidinoethyl)-N-iso-butyl-amide;
2-{2-[4-(Amino-hydroximino-methyl)phenyl]-ethyl}-1-methyl-benzimidazol-5-yl-carboxylic acid-[Nxe2x80x2-(cyclohexyl)-piperazide]; and, 2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylic acid-[Nxe2x80x2-(2-methyl-phenyl)-diazepide].
Apart from the abovementioned compounds of general formula (I) the present invention is also directed to compounds which are only converted into the therapeutically effective compounds of general formula (I) by the body after being taken by the patient, on the basis of a functionality which can be cleaved in vivo. Such compounds are known as prodrugs. According to another aspect the invention therefore relates to prodrugs of general formula (II)

 
wherein
R1 and R4 may be as hereinbefore defined and
R3 may have the meanings given hereinbefore or denotes C1-C4-alkyl, which is substituted by a group selected from the group comprising xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C4-alkyl)NH2 or xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C4-alkyl-phenyl)NH2;
R5 may denote hydroxy, xe2x80x94COOxe2x80x94C1-C8-alkyl or xe2x80x94COOxe2x80x94C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring may be substituted by C1-C4-alkyl or C1-C4-alkoxy,
and tautomers and pharmacologically acceptable acid addition salts thereof.
Preferred are prodrugs of general formula (II), wherein
R1, R3 and R4 may be as hereinbefore defined and
R5 may denote hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, benzyloxycarbonyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.
In another aspect the present invention relates to compounds of general formula (III)

 
wherein the groups R1, R3 and R4 may be as hereinbefore defined. The compounds of general formula (III) are valuable intermediate products for preparing the aminocarbonyl-substituted benzimidazole derivatives of general formula (I) according to the invention and the prodrugs of general formula (II) according to the invention.
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. Unless otherwise stated, the above terms propyl, butyl, pentyl, hexyl, heptyl and octyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
Examples of cycloalkyl groups with 3-8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Fluorine, chlorine, bromine or iodine is generally referred to as halogen.
Examples of N-linked cyclic groups of general formula NR3R4 include: pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine or diazepan, which may be substituted as specified in the definitions.
Examples of 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulphur as heteroatoms, include, unless otherwise stated in the definitions, furan, tetrahydrofuran, tetrahydrofuranon, xcex3-butyrolactone, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolan, dithiolan, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine, wherein the heterocyclic group may be substituted as stated in the definitions.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
Aminocarbonyl-substituted benzimidazole derivatives of formula (I) and the prodrugs of general formula (II) may be synthesised using the methods of synthesis known from the prior art. In this respect, attention is drawn to International Patent Application WO 98/37075 mentioned earlier, the contents of which are hereby referred to.
One possible method of obtaining the compounds according to the invention with the aid of and using conventional chemical methods of synthesis is diagrammatically shown hereinafter (Diagram 1).

 
In a first step (step i, Diagram 1) 4-amino-3-nitrobenzoic acid derivatives are synthesised, starting from 4-halo-3-nitro-benzoic acid derivatives, by aminolysis with suitably substituted primary amines. The reaction is carried out in suitable organic solvents such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone or optionally in water at ambient temperature or in a temperature range from 30-80xc2x0 C., preferably 40-50xc2x0 C. The aminobenzoic acid compounds thus obtained are converted by standard conventional methods into the corresponding alkylesters, preferably into the corresponding methylesters or ethylesters (step ii, Diagram 1). The reduction of the nitro group to the alkyl diaminobenzoates is preferably carried out by catalytic hydrogenation according to step iii (Diagram 1). The preferred catalyst is palladium. Palladium on charcoal (5%) is particularly preferred as the catalyst. By reacting the diaminobenzoates thus obtained with p-cyanophenylpropionic acid in the presence of dehydrating reagents, the benzimidazole heterocycle is formed according to step v (Diagram 1). The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane. Suitable dehydrating agents include, for example, isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, phosphorus oxychloride, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, ethyl 1,2-dihydro-2-ethoxy-quinoline-1-carboxylate (EEDQ), i-propylester 1,2-dihydro-2-i-propyloxy-quinolin-1-carboxylate (IIDQ), N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benztriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride. In some cases it may prove useful to add a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine. The reaction is normally carried out at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 110xc2x0 C.
The benzimidazole derivatives of general formula (III) which may be prepared according to step v (Diagram 1) are either obtainable directly from the abovementioned benzimidazole carboxylates or are obtained via the corresponding carboxylic acids or carboxylic acid halides.
If the carboxylic acid esters obtained in step iv (Diagram 1) are saponified under standard conditions (protic organic solvent such as methanol, ethanol or isopropanol, for example. optionally in the presence of water and in the presence of bases such as hydroxides or carbonates of alkali and alkaline earth metals), this leads to the corresponding free carboxylic acids. Usually, this saponification is carried out at temperatures between 0-40xc2x0 C., preferably at 10-30xc2x0 C. If desired, however, the synthesis may also be carried out at elevated temperature ( greater than 50xc2x0 C. to reflux temperature).
The preferred solvent according to the invention is a methanol-water mixture. The base used is preferably sodium hydroxide. The reaction of the resulting acid with the amines Hxe2x80x94NR3R4 to obtain the compounds of general formula (III) is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or in the corresponding amine Hxe2x80x94NR3R4, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, appropriately at temperatures of between 0 and 150xc2x0 C., preferably at temperatures of between 0 and 100xc2x0 C.,
The synthesis of the compounds of general formula (III) starting from the carboxylates obtained in Diagram 1 (step iv) or from the corresponding carboxylic acid chlorides is carried out either in the corresponding amine Hxe2x80x94NR3R4 as solvent, or with the amine Hxe2x80x94NR3R4 in the presence of a solvent such as methylene chloride, ether or ethyl acetate and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures of between 0 and 150xc2x0 C., preferably at temperatures of between 40 and 100xc2x0 C.
A compound of general formula (I) is obtained for example by treating a compound of general formula (III, Diagram 1, step vi) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol optionally mixed with another organic solvent such as for example chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium-salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures of between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. Alternatively, the compounds of general formula (I) may be obtained by reacting a compound of general formula (III) (Diagram 1, step vi) with sulphur nucleophiles such as e.g. hydrogen sulphide, ammonium or sodium sulphide, sodium hydrogen sulphide, carbon disulphide, thioacetamide or bistrimethylsilylthioether optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alkoxide in solvents such as methanol, ethanol, water, tetrahydrofuran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100xc2x0 C., and subsequently treating with a suitable methylating agent such as e.g. methyl iodide or dimethyl sulphate in a solvent such as acetonitrile or acetone at temperatures of between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and then treating with ammonia, ammonium carbonate or ammonium chloride in a suitable alcohol, such as for example methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
Moreover, the compounds of general formula (I) according to the invention may be obtained by treating a compound of general formula (III) with lithium hexamethyldisilazide in a suitable organic solvent such as e.g. tetrahydrofuran at temperatures of between xe2x88x9220 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and then hydrolysing with dilute hydrochloric acid at 0-5xc2x0 C.
Another alternative method of obtaining compounds of general formula (I) is by treating a compound of general formula (III) with ammonium chloride and trimethylaluminium in a suitable organic solvent such as e.g. toluene at temperatures of between 20 and 150xc2x0 C., but preferably at 110xc2x0 C.
A compound of general formula (II) is obtained for example by treating a compound of general formula (III, Diagram 1, step vii) with hydroxylamine in the presence of carbonates or alkoxides of the alkali or alkaline earth metals in solvents such as methanol, ethanol, n-propanol or isopropanol optionally mixed with dioxane or tetrahydrofuran. The alkoxides may be prepared from the respective alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100xc2x0 C., most preferably at the boiling temperature of the solvent used.
Compounds of general formula (II) may alternatively be prepared by treating a compound of general formula (III, Diagram 1, step vii) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium-salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures of between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently treating with hydroxylamine in the presence of bases in a suitable alcohol, such as methanol, ethanol, isopropanol etc. at temperatures of between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
A compound of general formula (I) may be obtained for example by treating a compound of general formula (II, Diagram 1, step viii) with hydrogen in the presence of hydrogenation catalysts such as Raney nickel or rhodium/aluminium oxide in water or methanol, optionally with the addition of acids such as hydrochloric acid or methanesulphonic acid or by treating with hydrogen in the presence of palladium/charcoal in acetic acid/acetic anhydride at 20-50xc2x0 C. and 1-5 bar hydrogen pressure, preferably at ambient temperature and normal pressure.
Acyl- or alkoxycarbonyl prodrugs of the compound of general formula (I) are obtained by reacting the compounds of general formula (I) with the corresponding acid chlorides in the presence of bases such as e.g. triethylamine, N-methylmorpholine, diethylisopropylamine or DBU in a suitable solvent such as methylene chloride, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethyl sulphoxide.
Alternatively to the method described above the compounds according to the invention may also be obtained on a polymeric carrier by means of a solid phase synthesis. The method of production by solid phase synthesis, as shown by way of example in Diagram 2 in a manner which must not be regarded as restricting the core of the invention, is of particular interest for those compounds according to the invention wherein the group R3 is terminally amino-substituted.

 
In a first step (Diagram 2, step i) a resin-bound diamine is reacted. The resins which may be used are usually trityl, 2-chlorotrityl, 4-methoxytrityl resins with polymer matrices of crosslinked polystyrene or Tentagel or Synphase(trademark) crowns. In order to carry out the synthesis step according to Diagram 2 (step i) the same procedure is used as hereinbefore, according to the invention. 2-4 equivalents of the diamine, based on the resin charge, are dissolved in an organic solvent selected from the group comprising dichloromethane, tetrahydrofuran, 1,2-dichloroethane or dimethylformamide. The solution is added to the trityl resin and stirred for 2-16 h at ambient temperature. Then the resin is filtered off and washed several times with dry pyridine or a mixture of dichloromethane/diisopropylamine and dichloromethane or dry diethylether. The resin is dried in vacuo until a constant weight is obtained.
In a second step (Diagram 2, step ii) the diamine coupled to the resin is reacted in a reductive amination with the aldehydes R4xe2x80x94CHO, wherein R4 may have the meanings given hereinbefore. The following procedure is used for this. 2-10 Equivalents of the aldehyde R4xe2x80x94CHO, dissolved in tetramethyl orthoformate/dichloromethane or dichloromethane or dichloromethane/dimethylformamide or dimethylformamide or 1,2-dichloromethane, are added to diamine-charged resin, suspended in tetramethyl orthoformate or dichloromethane, dimethylformamide, 1,2-dichloromethane, 1-methyl-2-pyrrolidone (each with added tetramethyl orthoformate) and shaken for 2-12 h at 0-30xc2x0 C. Then the resin is washed and mixed with a solution of sodium triacetoxyborohydride or sodium cyanoborohydride in dichloromethane or DMF or 1,2-dichloromethane at 0-30xc2x0 C. and agitated for 2-24 h. Alternatively the aldehyde and the reducing agent may be added directly to the resin.
In the third step the amine coupled to the resin is reacted with 4-chloro-3-nitrobenzoylchloride in an acylating reaction (Diagram 2, step iii). The following procedure is used for this. The resin is suspended in dichloromethane or dimethylformamide or 1,2-dichloromethane or 1-methyl-2-pyrrolidone or tetrahydrofuran with the addition of a base such as triethylamine or diisopropylethylamine or pyridine and combined at ambient temperature with a solution of 4-chloro-3-nitro-benzoylchlorid in dichloromethane or 1,2-dichloroethane or 1-methyl-2-pyrrolidone or dimethylformamide or tetrahydrofuran and shaken for 1-12 h at ambient temperature. Then the mixture is filtered and washed with various solvents. Alternatively to the method shown by way of example in Diagram 2, it is possible to use 4-fluoro-3-nitro-benzoylchloride, for example, instead of the 4-chloro-3-nitro-benzoylchloride.
There is then a Nucleophilic Substitution at the benzoic acid amide coupled to the resin by the primary amines R1xe2x80x94NH2.(Diagram 2, step iv). The following procedure is used for this, according to the invention. The resin, suspended in diisopropylethylamine solution or in 1-methyl-2-pyrrolidone or dimethylformamide (20% v/v), is combined with a solution of an amine R1xe2x80x94NH2 in 1-methyl-2-pyrrolidone or dimethylformamide and heated for 2-24 h in a temperature range from 50-110xc2x0 C. After cooling to ambient temperature the resin is filtered off and washed with various solvents.
The reduction of the nitro group leads according to step v (Diagram 2) to the diaminobenzoic acid amides coupled to the resin. The following procedure is used for this, according to the invention. The resin is suspended in dimethylformamide or 1-methyl-2-pyrrolidone, combined with 5-50 equivalents of 1.0 M SnCl2 solution in dimethylformamide or in 1-methyl-2-pyrrolidone and shaken for 12-48 h at ambient temperature. Then the resin is filtered off and washed intensively with various solvents. Alternatively to the reduction with the abovementioned SnCl2 solutions, the reaction may also be carried out for example with sodium borohydride/Cu(acac)2 (cat.) or Na2S2O4 in protic organic solvents such as alcohols, preferably in ethanol.
By reacting with the aldehydes R2xe2x80x94C6H4xe2x80x94CH2CH2xe2x80x94CHO according to step vi (Diagram 2) the resin-coupled benzimidazole heterocycles are obtained by oxidative cyclisation. The following procedure is used for this, according to the invention. The resin is suspended in tetrahydrofuran or dioxane or 1-methyl-2-pyrrolidone, combined with a solution of an aldehyde R2xe2x80x94C6H4xe2x80x94CH2CH2xe2x80x94CHO in THF or dioxane or 1-methyl-2-pyrrolidone and shaken for 12-48 h at ambient temperature in oxygen from the air. Then the resin is filtered off and washed.
After the cleaving of the resin, the compounds of general formula (I) according to the invention can thus be obtained (Diagram 2, step vii). The following procedure is used according to the invention for the cleaving. The resin is shaken with trifluoroacetic acid (10-70% v/v) in dichloromethane for 1 h at ambient temperature and suction filtered. Then the resin remaining is once again combined with trifluoroacetic acid (10-70% v/v) in dichloromethane, suction filtered, and the combined filtrates are evaporated down in vacuo. After the resin residue has been treated with a mixture of dichloromethane/methanol it is filtered off after 1 h shaking at ambient temperature.
The filtrates and the residues obtained are combined and evaporated to dryness in vacuo.